The lymphocytic ionotropic purinergic P2X receptors (P2X1R-P2X7R, or P2Xs) sense the ATP, released during cell damage-activation, thus regulating T-cell activation. We aim to define the role of P2Xs during islet allograft rejection and to establish a novel anti-P2X strategy to achieve long-term islet allograft function. Our data demonstrate that P2X1R and P2X7R are induced in islet graft-infiltrating T-cells in a model of allogeneic islet transplantation (BALB/c islets transplanted into hyperglycemic C57BL/6 mice), but only P2X7R is increasingly expressed during alloimmune response, while P2X1R is augmented in both allogeneic and syngeneic transplantation. In vivo short-term P2X7R targeting (using periodate-oxidized ATP [oATP], 250 Μg day 0 to day 15 i.p.) delayed islet allograft rejection (Mean Survival Time [MST]: oATP treated=22 days vs. Untreated=14 days, n=10; p=0.0001) with indefinite graft survival achieved in 3 out of 10 mice, reduced the frequency of Th1/Th17 cells, and induced hyporesponsiveness toward donor antigens (IFN-Γ-producing cells: oATP-treated day 14=117±9 vs. untreated day 14=418±26, n=5; p<0.0001). oATP-treated mice also displayed preserved islet grafts with reduced Th1 transcripts. P2X7R targeting and Rapamycin synergized in inducing long-term islet function in 80% of transplanted mice and resulted in reshaping of the recipient immune system. In vitro P2X7R targeting using oATP reduced T-cell activation and diminished Th1/Th17 cytokine production. PBMC obtained from long-term islet-transplanted patients showed an increased percentage of P2X7R+CD4+ T-cells compared to controls and in particular P2X7R expression increased in memory T-cells (CD45RO+ T-cells); in vitro, a reduction in the number of IFN-Γ-producing cells in response to allogeneic stimulation was observed with the human specific P2X7R-inhibitor CE-224535 in human PBMC (IFN-Γ-producing cells: CE-224535-treated= 29±1 vs. control= 51±3, n=5; p=0.003) confirming potential for clinical islet transplantation. The beneficial effects of oATP treatment revealed a role for the purinergic system in islet allograft rejection, and the targeting of P2X7R is a novel strategy to induce long-term islet allograft function.
To cite this abstract in AMA style:Vergani A, Bassi R, D'Addio F, Fotino C, Tezza S, Molano R, Soleti A, Maffi P, Secchi A, Ricordi C, Sayegh M, Pileggi A, Fiorina P. Effect of the Purinergic Inhibitor Oxidized-ATP in a Model of Islet Allograft Rejection [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/effect-of-the-purinergic-inhibitor-oxidized-atp-in-a-model-of-islet-allograft-rejection/. Accessed October 20, 2020.
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